Linear furocoumarins, also known as psoralens, have been used in combination with ultraviolet light for centuries in cosmetics and for the treatment of proliferative skin diseases such as, for example, vitiligo, eczema, mycosis fungoides, and psoriasis. Terms such as photosensitization, photochemotherapy, photopheresis and PUVA (psoralens ultra violet A radiation where UVA is ultraviolet light A) are commonly used to refer to such methods. Recently it was discovered that by modifying the administration of psoralen and ultraviolet light to an offending condition, psoralens could be used to treat cancer (e.g., T cell lymphoma), autoimmune diseases, and microbial infection.
The basic structure of psoralen, with the ring numbering structure used herein, is shown below:
All psoralens contain two photo-activatable functional groups that absorb in the UVA range. These are an aryl-conjugated unsaturated pyrone (or the coumarin portion) and an aryl-conjugated vinyl ether (or the furan portion). Commercially available psoralens are typically highly lipophilic, non-nitrogenous, uncharged small molecules with minimal water solubility. Commercial psoralens are used in over-the-counter cosmetic creams, prescription pharmaceuticals, and as investigational candidates for many of the uses described above. Examples of commercial psoralens used cosmetically and medically include methoxysalen (also referred to as xanthotoxin, 8-methoxypsoralen or 8-MOP), trisoralen (also called 4,5′,8-trimethylpsoralen, TMP, or trioxsalen), and bergaptan (alternatively referred to as 5-methoxypsoralen or 5-MOP). The phototherapeutic action of psoralens has been discussed for example, by J. E. Hearst, “Photochemistry of the Psoralens,” Chemical Research in Toxicology, 2, 69, 1989 and T. F. Anderson and J. J. Voorhees, Annual Reviews of Pharmacol. and Toxicol., vol. 10, p. 177, 1982. According to these articles, the highly lipophilic psoralens penetrate the target cell's membrane, intercalate into nuclear DNA, and photo crosslink the double helix through bis-cyclobutanes generated from the 3,4-double bond and the 4′,5′-double bond [see numbering shown supra] to double bonds in DNA's pyrimidine bases. Thus, because the crosslinked DNA is unable to uncoil and function as a template for replication and new gene expression, the target cell is rendered unable to proliferate or non-viable.
In many applications the pharmacological utility of the parent psoralens is compromised by their insolubility in aqueous biological fluids.
Various routes for introduction of an aminomethyl [—CH2—NH2] group onto the furan ring have been described. However, while these basic loci can then be converted to water-soluble salts, the molecular architecture of the psoralens is altered by pendant attachments at C-5 and C-4.
Alternative methods to obtain furan-substituted amino psoralens are described by Kaufman (U.S. Pat. No. 4,294,822 (1981)), Hearst (U.S. Pat. No. 4,124,598 (1978)), and Heindel (U.S. Pat. No. 4,950,770 (1990)).
In the present invention water-soluble dimethyl amino ethyl ether psoralen compounds and methods for producing and using such N,N-dimethylaminoethyl ether psoralen compounds are provided.